Molecular docking and dynamics studies to identify novel active compounds targeting potential breast cancer receptor proteins from an indigenous herb Euphorbia thymifolia Linn

Abstract

Background Breast cancer has become the most prevalent disease and its incidence has almost doubled in the Indian population. This increased burden demands new targeted therapies with novel compounds either synthetically produced or derived from indigenous plants, which could be a promising approach for the development of drugs. Euphorbia thymifolia L is a widely growing tropical herb that has been reported to have various ethnopharmacological properties, including anticancer properties. Therefore, the aim of the present study was to screen the phytoconstituents and identify the active compounds present in the methanolic extract of E. thymifolia (ME.ET) as ligands to inhibit potential protein targets implicated in breast cancer using an In-silico approach. Methods ME.ET was subjected to GC-MS analysis to screen the phytoconstituents, and the identified compounds were docked with protein targets such as extracellular signal-regulated kinases (ERK1), a serine/threonine kinase-1(AKT1), human epidermal growth factor 2 (HER2), estrogen receptor (ER), maternal embryonic leucine zipper kinase (MELK), polo-like kinase-1(PLK1), and protein tyrosine kinase (PTK6). Compounds with good docking scores were further subjected to dynamic studies to understand the protein ligand binding stability, ligand pathway calculation, and molecular mechanics energies combined with Poisson-Boltzmann (MM/PBSA) calculations using the Schrodinger suite. Results GC-MS analysis revealed the presence of 245 phytoconstituents, 219 of which were unique. When subjected to docking, these phytocompounds, namely 3,6,9,12-tetraoxatetradecane-1,14-diyl dibenzoate (TTDB) and succinic acid, 2-(dimethylamino) ethyl 4-isopropylphenyl ester (SADPE), showed good docking scores. Molecular dynamics studies showed a high affinity and low binding energy for TTDB with HER2, ERK1, and SADPE with ER. Conclusions Hence, in this study, we identified two lead compounds in E.thymifolia linn. Further invitro and invivo anticancer studies can be performed to confirm these results and to understand the molecular mechanism by which they exhibit anticancer activity against breast cancer.